The present invention relates to substituted 2-(2,6-dioxopiperidin-3-yl)-phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines, the method of reducing levels of tumor necrosis factor xcex1 and treating inflammatory and autoimmune diseases in a mammal through the administration thereof, and to pharmaceutical compositions of such derivatives.
Tumor necrosis factor xcex1, or TNFxcex1, is a cytokine which is released primarily by mononuclear phagocytes in response to a number immunostimulators. When administered to animals or humans, it causes inflammation, fever, cardiovascular effects, hemorrhage, coagulation. and acute phase responses similar to those seen during acute infections and shock states. Excessive or unregulated TNFxcex1 production thus has been implicated in a number of disease conditions. These include endotoxemia and/or toxic shock syndrome {Tracey et al., Nature 330, 662-664 (1987) and Hinshaw et al., Circ. Shock 30, 279-292 (1990)}; cachexia {Dezube et al., Lancet, 335 (8690), 662 (1990)} and Adult Respiratory Distress Syndrome where TNFxcex1 concentration in excess of 12,000 pg/mL have been detected in pulmonary aspirates from ARDS patients {Millar et al., Lancet 2(8665), 712-714 (1989)}. Systemic infusion of recombinant TNFxcex1 also resulted in changes typically seen in ARDS {Ferrai-Baliviera et al., Arch. Surg. 124(12), 1400-1405 (1989)}.
TNFxcex1 appears to be involved in bone resorption diseases, including arthritis. When activated, leukocytes will produce bone-resorption, an activity to which the data suggest TNFxcex1 contributes. {Bertolini et al., Nature 319, 516-518 (1986) and Johnson et al., Endocrinology 124(3), 1424-1427 (1989).} TNFxcex1 also has been shown to stimulate bone resorption and inhibit bone formation in vitro and in vivo through stimulation of osteoclast formation and activation combined with inhibition of osteoblast function. Although TNFxcex1 may be involved in many bone resorption diseases, including arthritis, the most compelling link with disease is the association between production of TNFxcex1 by tumor or host tissues and malignancy associated hypercalcemia {Calci. Tissue Int. (US) 46(Suppl.), S3-10 (1990)}. In Graft versus Host Reaction, increased serum TNFxcex1 levels have been associated with major complication following acute allogenic bone marrow transplants {Holler et al., Blood, 75(4), 1011-1016 (1990)}.
Cerebral malaria is a lethal hyperacute neurological syndrome associated with high blood levels of TNFxcex1 and the most severe complication occurring in malaria patients. Levels of serum TNFxcex1 correlated directly with the severity of disease and the prognosis in patients with acute malaria attacks {Grau et al., N. Engl. J. Med. 320(24), 1586-1591 (1989)}.
Macrophage-induced angiogenesis is known to be mediated by TNFxcex1. Leibovich vich et al. {Nature, 329, 630-632 (1987)} showed TNFxcex1 induces in vivo capillary blood vessel formation in the rat cornea and the developing chick chorioallantoic membranes at very low doses and suggest TNFxcex1 is a candidate for inducing angiogenesis in inflammation, wound repair, and tumor growth. TNFxcex1 production also has been associated with cancerous conditions, particularly induced tumors {Ching et al., Brit. J. Cancer, (1955) 72, 339-343, and Koch, Progress in Medicinal Chemistry, 22, 166-242 (1985)}.
TNFxcex1 also plays a role in the area of chronic pulmonary inflammatory diseases. The deposition of silica particles leads to silicosis, a disease of progressive respiratory failure caused by a fibrotic reaction. Antibody to TNFxcex1 completely blocked the silica-induced lung fibrosis in mice {Pignet et al., Nature, 344:245-247 (1990)}. High levels of TNFxcex1 A production (in the serum and in isolated macrophages) have been demonstrated in animal models of silica and asbestos induced fibrosis {Bissonnette et al., Inflammation 13(3), 329-339 (1989)}. Alveolar macrophages from pulmonary sarcoidosis patients have also been found to spontaneously release massive quantities of TNFxcex1 as compared with macrophages from normal donors {Baughman et al., J. Lab. Clin. Med. 1 15(1), 36-42 (1990)}.
TNFxcex1 is also implicated in the inflammatory response which follows reperfusion, called reperfusion injury, and is a major cause of tissue damage after loss of blood flow {Vedder et al., PNAS 87, 2643-2646 (1990)}. TNFxcex1 also alters the properties of endothelial cells and has various pro-coagulant activities, such as producing an increase in tissue factor pro-coagulant activity and suppression of the anticoagulant protein C pathway as well as down-regulating the expression of thrombomodulin {Sherry et al., J. Cell Biol. 107, 1269-1277 (1988)}. TNFxcex1 has pro-inflammatory activities which together with its early production (during the initial stage of an inflammatory event) make it a likely mediator of tissue injury in several important disorders including but not limited to, myocardial infarction, stroke and circulatory shock. Of specific importance may be TNFxcex1-induced expression of adhesion molecules, such as intercellular adhesion molecule (ICAM) or endothelial leukocyte adhesion molecule (ELAM) on endothelial cells {Munro et al., Am. J. Path. 135(1), 121-132 (1989)}.
TNFxcex1 blockage with monoclonal anti-TNFxcex1 antibodies has been shown to be beneficial in rheumatoid arthritis {Elliot et al., Int. J. Pharmac. 1995 17(2), 141-145} and Crohn""s disease {von Dullemen et al., Gastroenterology, 1995 109(1), 129-135}.
Moreover, it now is known that TNFxcex1 is a potent activator of retrovirus replication including activation of HIV-1. {Duh et al., Proc. Nat. Acad. Sci. 86, 5974-5978 (1989); Poll et al., Proc. Nat. Acad. Sci. 87, 782-785 (1990); Monto et al., Blood 79, 2670 (1990); Clouse et al., J. Immunol. 142, 431-438 (1989); Poll et al., AIDS Res. Hum. Retrovirus, 191-197 (1992)}. AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV). At least three types or strains of HIV have been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence of HIV infection, T-cell mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HIV entry into the T lymphocyte requires T lymphocyte activation. Other viruses, such as HIV-1, HIV-2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication. Cytokines, specifically TNFxcex1, are implicated in activated T-cell mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity such as by prevention or inhibition of cytokine production, notably TNFxcex1, in an HIV-infected individual assists in limiting the maintenance of T lymphocyte caused by HIV infection.
Monocytes, macrophages, and related cells, such as kupffer and glial cells, also have been implicated in maintenance of the HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. {Rosenberg et al., The Immunopathogenesis of HIV Infection, Advances in Immunology, 57 (1989)}. Cytokines, such as TNFxcex1, have been shown to activate HIV replication in monocytes and/or macrophages {Poli et al., Proc. Natl. Acad. Sci., 87, 782-784 (1990)}, therefore, prevention or inhibition of cytokine production or activity aids in limiting HIV progression for T cells. Additional studies have identified TNFxcex1 as a common factor in the activation of HIV in vitro and has provided a clear mechanism of action via a nuclear regulatory protein found in the cytoplasm of cells (Osborn, et al., PNAS 86 2336-2340). This evidence suggests that a reduction of TNFxcex1 synthesis may have an antiviral effect in HIV infections, by reducing the transcription and thus virus production.
AIDS viral replication of latent HIV in T cell and macrophage lines can be induced by TNFxcex1 {Folks et al., PNAS 86, 2365-2368 (1989)}. A molecular mechanism for the virus inducing activity is suggested by TNFxcex1""s ability to activate a gene regulatory protein (NFxcexaB) found in the cytoplasm of cells, which promotes HIV replication through binding to a viral regulatory gene sequence (LTR) {Osborn et al., PNAS 86, 2336-2340 (1989)}. TNFxcex1 in AIDS associated cachexia is suggested by elevated serum TNFxcex1 and high levels of spontaneous TNFxcex1 production in peripheral blood monocytes from patients {Wright et al., J. Immunol. 141(1), 99-104 (1988)}. TNFxcex1 has been implicated in various roles with other viral infections, such as the cytomegalia virus (CMV), influenza virus, adenovirus, and the herpes family of viruses for similar reasons as those noted.
The nuclear factor xcexaB (NFxcexaB) is a pleiotropic transcriptional activator (Lenardo, et al., Cell 1989, 58, 227-29). NFxcexaB has been implicated as a transcriptional activator in a variety of disease and inflammatory states and is thought to regulate cytokine levels including but not limited to TNFxcex1 and also to be an activator of HIV transcription (Dbaibo, et al., J. Biol. Chem. 1993, 17762-66; Duh et al., Proc. Natl. Acad. Sci. 1989, 86, 5974-78; Bachelerie et al., Nature 1991, 350, 709-12; Boswas et aL., J. Acquired Immune Deficiency Syndrome 1993, 6, 778-786; Suzuki et al., Biochem. And Biophys. Res. Comm. 1993, 193, 277-83; Suzuki et al., Biochem. And Biophys. Res Comm. 1992, 189, 1709-15; Suzuki et al., Biochem. Mol. Bio. Int. 1993, 31(4), 693-700; Shakhov et al., Proc. Natl. Acad. Sci. USA 1990, 171, 35-47; and Staal et al., Proc. Natl. Acad. Sci. USA 1990, 87, 9943-47). Thus, inhibition of NFxcexaB binding can regulate transcription of cytokine gene(s) and through this modulation and other mechanisms be useful in the inhibition of a multitude of disease states. The compounds described herein can inhibit the action of NFxcexaB in the nucleus and thus are useful in the treatment of a variety of diseases including but not limited to rheumatoid arthritis, rheumatoid spondylitis, osteo-arthritis, other arthritic conditions, septic shock, septis, endotoxic shock, graft versus host disease, wasting, Crohn""s disease, inflammatory bowel disease, ulcerative colitis, multiple sclerosis, systemic lupus erythrematosis, ENL in leprosy, HIV, AIDS, and opportunistic infections in AIDS. TNFxcex1 and NFxcexaB levels are influenced by a reciprocal feedback loop. As noted above, the compounds of the present invention affect the levels of both TNFxcex1 and NFxcexaB.
Many cellular functions are mediated by levels of adenosine 3xe2x80x2,5xe2x80x2-cyclic monophosphate (cAMP). Such cellular functions can contribute to inflammatory conditions and diseases including asthma, inflammation, and other conditions (Lowe and Cheng, Drugs of the Future, 17(9), 799-807, 1992). It has been shown that the elevation of cAMP in inflammatory leukocytes inhibits their activation and the subsequent release of inflammatory mediators, including TNFxcex1 and NFxcexaB. Increased levels of cAMP also leads to the relaxation of airway smooth muscle.
Decreasing TNFxcex1 levels and/or increasing cAMP levels thus constitutes a valuable therapeutic strategy for the treatment of many inflammatory, infectious, immunological or malignant diseases. These include but are not restricted to septic shock, sepsis, endotoxic shock, hemodynamic shock and sepsis syndrome, post ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer, autoimmune disease, opportunistic infections in AIDS, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, other arthritic conditions, Crohn""s disease, ulcerative colitis, multiple sclerosis, systemic lupus erythrematosis, ENL in leprosy, radiation damage, and hyperoxic alveolar injury. Prior efforts directed to the suppression of the effects of TNFxcex1 have ranged from the utilization of steroids such as dexamethasone and prednisolone to the use of both polyclonal and monoclonal antibodies {Beutler et al., Science 234, 470-474 (1985); WO 92/11383}.
The present invention is based on the discovery that certain classes of non-polypeptide compounds more fully described herein decrease the levels of TNFxcex1.
In particular, the invention pertains to compounds of the formula: 
in which:
one of X and Y is Cxe2x95x90O and the other of X and Y is Cxe2x95x90O or CH2;
(i) each of R1, R2 , R3, and R4, independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1, R2, R3, and R4 is xe2x80x94NHR5 and the remaining of R1, R2, R3, and R4 are hydrogen;
R5 is hydrogen or alkyl of 1 to 8 carbon atoms;
R6 is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro, or fluoro;
R7 is m-phenylene or p-phenylene or xe2x80x94(CnH2n)xe2x80x94 in which n has a value of 0 to 4;
each of R8 and R9 taken independently of the other is hydrogen or alkyl of 1 to 8 carbon atoms, or R8 and R9 taken together are tetramethylene, pentamethylene, hexamethylene, or xe2x80x94CH2CH2[X]X1CH2CH2xe2x80x94 in which [X]X1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94;
R10 is hydrogen, alkyl of to 8 carbon atoms, or phenyl; and
(b) the acid addition salts of said compounds which contain a nitrogen atom capable of being protonated.
A first preferred group of compounds are those of Formula I in which at least one of of R1, R2, R3, R4, and R6 is other than hydrogen. Among these, a preferred group are those compounds in which each of R1, R2, R3, and R4, independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms; R6 is hydrogen, methyl, ethyl, or propyl; ; each of R8 and R9 taken independently of the other is hydrogen or methyl; and R10 is hydrogen. Of these compounds, a preferred subgroup are those compounds in which R7 is m-phenylene or p-phenylene while a second preferred subgroup are those compounds in which R7xe2x80x94(CnH2n)xe2x80x94 in which n has a value of 0 to 4.
A further preferred group of compounds are those of Formula I in which one of R1, R2, R3, and R4 is xe2x80x94NH2 and the remaining of R1, R2, R3, and R4 are hydrogen; R6 is hydrogen, methyl, ethyl, or propyl; each of R8 and R9 taken independently of the other is hydrogen or methyl; and R10 is hydrogen. Of these compounds, a first preferred subgroup are those compounds in which R7 is m-phenylene or p-phenylene while a second preferred subgroup are those compounds in which R7xe2x80x94(CnH2n)xe2x80x94 in which n has a value of 0 to 4.
The term alkyl denotes a univalent saturated branched or straight hydrocarbon chain containing from 1 to 8 carbon atoms. Representative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. Alkoxy refers to an alkyl group bound to the remainder of the molecule through an ethereal oxygen atom. Representative of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. Preferably R1, R2, R3, and R4 are chloro, fluoro, methyl or methoxy.
The compounds of Formula I are used, under the supervision of qualified professionals, to inhibit the undesirable effects of TNFxcex1. The compounds can be administered orally, rectally, or parenterally, alone or in combination with other therapeutic agents including antibiotics, steroids, etc., to a mammal in need of treatment.
The compounds of the present invention also can be used topically in the treatment or prophylaxis of topical disease states mediated or exacerbated by excessive TNFxcex1 production, respectively, such as viral infections, such as those caused by the herpes viruses, or viral conjunctivitis, psoriasis, atopic dermatitis, etc.
The compounds also can be used in the veterinary treatment of mammals other than humans in need of prevention or inhibition of TNFxcex1 production. TNFxcex1 mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections. Examples include feline immunodeficiency virus, equine infectious anaemia virus, caprine arthritis virus, visna virus, and maedi virus, as well as other lentiviruses.
The compounds can be prepared through an initial reaction of formaldehyde with an intermediate of the formula: 
in which
X and Y are as defined above;
each of R1, R2, R3, and R4, independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1, R2, R3, and R4 is nitro or protected amino and the remaining of R1, R2, R3, and R4 are hydrogen; and
R6 is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro, or fluoro.
The resulting N-hydroxymethyl intermediate of Formula II then is coupled with a carboxylic acid derivative of Formula IV using methods which are known in general: 
in which Hal is a reactive halogen such as chloro, bromo, or iodo.
Protecting groups utilized herein denote groups which generally are not found in the final therapeutic compounds but which are intentionally introduced at some stage of the synthesis in order to protect groups which otherwise might be altered in the course of chemical manipulations. Such protecting groups are removed at a later stage of the synthesis and compounds bearing such protecting groups thus are of importance primarily as chemical intermediates (although some derivatives also exhibit biological activity). Accordingly the precise structure of the protecting group is not critical. Numerous reactions for the formation and removal of such protecting groups are described in a number of standard works including, for example, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, Plenum Press, London and New York, 1973; Greene, Th. W. xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Wiley, N.Y., 1981; xe2x80x9cThe Peptidesxe2x80x9d, Vol. I, Schrxc3x6der and Lubke, Academic Press, London and New York, 1965; xe2x80x9cMethoden der organischen Chemiexe2x80x9d, Houben-Weyl, 4th Edition, Vol.15/I, Georg Thieme Verlag, Stuttgart 1974, the disclosures of which are incorporated herein by reference.
An amino group can be protected as an amide utilizing an acyl group which is selectively removable under mild conditions, especially benzyloxycarbonyl, formyl, or a lower alkanoyl group which is branched in 1- or xcex1 position to the carbonyl group, particularly tertiary alkanoyl such as pivaloyl, a lower alkanoyl group which is substituted in the position a to the carbonyl group, as for example trifluoroacetyl.
Coupling agents include such reagents as dicyclohexylcarbodimide and N,Nxe2x80x2-carbonyldiimidazole.
Following coupling, compounds of Formula V can be aminated in a convention manner, as for example with an amine in the presence of sodium iodide.
Alternatively, a compound of Formula III is allowed to react with a protected aminocarboxylic acid of Formula IVA: 
in which Z is a protected amino group.
Following this coupling, the amino protecting group Z is removed.
In the foregoing reactions when one of R1, R2, R3, and R4 is nitro, it can be converted to an amino group by catalytic hydrogenation. Alternatively, if one of R1, R2, R3, and R4 is protected amino, the protecting group can be cleaved to yield the corresponding compound in which one of R1, R2, R3, and R4 is amino.
In addition to serving as intermediates, certain other compound of Formula IIA are themselves biologically active in reducing levels of tumor necrosis factor xcex1 in a mammal. These compounds are those of the formula: 
in which:
one of X and Y is Cxe2x95x90O and the other of X and Y is Cxe2x95x90O or CH2;
(i) each of R1, R2, R3, and R4, independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1, R2, R3, and R4 is xe2x80x94NHR5 and the remaining of R1, R2, R3, and R4 are hydrogen;
R5 is hydrogen, alkyl of 1 to 8 carbon atoms, or COxe2x80x94R7xe2x80x94CH(R10)NR8R9 in which each of R7, R8, R9, and R10 is as herein defined; and
R6 is alkyl of 1 to 8 carbon atoms, benzo, chloro, or fluoro.
Certain of the intermediates of Formula IIA are described in copending applications Ser. Nos. 08/690,258, and 08/701,494, the disclosures of which are incorporated herein by reference. In addition, an alkyl o-bromomethylbenzoate which is appropriately substituted with R1, R2, R3, and R4 substituents is allowed to react with an xcex1-R6-substituted xcex1-aminoglutarimide salt in the presence of an acid acceptor such as triethyl amine to yield compounds in which one of X and Y is Cxe2x95x90O and the other is CH2.
Compounds of Formula IIA in which X and Y are both Cxe2x95x90O also can be prepared by allowing a phthalic anhydride which is appropriately substituted with R1, R2, R3, and R4 to react with an xcex1-R6-substituted xcex1-aminoglutarimide salt in the presence of acetic acid and sodium acetate.
The xcex1-R6-substituted xcex1-aminoglutarimide salt utilized in the foregoing reactions can be obtained by cyclizing an xcex1-R6-substituted glutamine in which the amino group is protected. The cyclization can be conducted for example with N,Nxe2x80x2-carbonyldiimidazole in the presence of an acid acceptor such as dimethylaminopyridine. Upon completion of the reaction, the protecting group can be removed in an appropriate fashion. Solely by way of example, if the protecting group is the N-benzyloxycarbonyl group, it can be removed by catalytic hydrogenation. The xcex1-R6-substituted glutamines in turn can be prepared by treating an xcex1-R6-substituted glutamic acid anhydride, in which the amino group is protected, with ammonia. Finally, the xcex1-R6-substituted glutamic acid anhydride can be obtained from the corresponding xcex1-R6-substituted glutamic acid with acetic anhydride.
The compounds of Formulas I and IIB possess a center of chirality and can exist as optical isomers. Both the racemates of these isomers and the individual isomers themselves, as well as diastereomers when there are two chiral centers, are within the scope of the present invention. The racemates can be used as such or can be separated into their individual isomers mechanically as by chromatography using a chiral absorbant. Alternatively, the individual isomers can be prepared in chiral form or separated chemically from a mixture by forming salts with a chiral acid, such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, xcex1-bromocamphoric acid, methoxyacetic acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, and the like, and then freeing one or both of the resolved bases, optionally repeating the process, so as obtain either or both substantially free of the other; i.e., in a form having an optical purity of  greater than 95%.
The present invention also pertains to the physiologically acceptable non-toxic acid addition salts of the compounds of Formulas I and IIB. Such salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulphonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embonic acid, enanthic acid, and the like.
Oral dosage forms include tablets, capsules, dragees, and similar shaped, compressed pharmaceutical forms containing from 1 to 100 mg of drug per unit dosage. Isotonic saline solutions containing from 20 to 100 mg/mL can be used for parenteral administration which includes intramuscular, intrathecal, intravenous and intra-arterial routes of administration. Rectal administration can be effected through the use of suppositories formulated from conventional carriers such as cocoa butter.
Pharmaceutical compositions thus comprise one or more compounds of Formulas I IIB associated with at least one pharmaceutically acceptable carrier, diluent or excipient. In preparing such compositions, the active ingredients are usually mixed with or diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule or sachet. When the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. Examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia. calcium silicate, microcrystalline cellulose, polyvinylpyrrolidinone, cellulose, water, syrup, and methyl cellulose, the formulations can additionally include lubricating agents such as talc, magnesium stearate and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydroxybenzoates, sweetening agents or flavoring agents.
The compositions preferably are formulated in unit dosage form, meaning physically discrete units suitable as a unitary dosage, or a predetermined fraction of a unitary dose to be administered in a single or multiple dosage regimen to human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient. The compositions can be formulated so as to provide an immediate, sustained or delayed release of active ingredient after administration to the patient by employing procedures well known in the art.
Oral dosage forms include tablets, capsules, dragees, and similar shaped, compressed pharmaceutical forms containing from 1 to 100 mg of drug per unit dosage. Isotonic saline solutions containing from 20 to 100 mg/mL can be used for parenteral administration which includes intramuscular, intrathecal, intravenous and intra-arterial routes of administration. Rectal administration can be effected through the use of suppositories formulated from conventional carriers such as cocoa butter.
Pharmaceutical compositions thus comprise one or more compounds of Formula I associated with at least one pharmaceutically acceptable carrier, diluent or excipient. In preparing such compositions, the active ingredients are usually mixed with or diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule or sachet. When the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. Examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidinone, cellulose, water, syrup, and methyl cellulose, the formulations can additionally include lubricating agents such as talc, magnesium stearate and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydroxybenzoates, sweetening agents or flavoring agents.
The compositions preferably are formulated in unit dosage form, meaning physically discrete units suitable as a unitary dosage, or a predetermined fraction of a unitary dose to be administered in a single or multiple dosage regimen to human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient. The compositions can be formulated so as to provide an immediate, sustained or delayed release of active ingredient after administration to the patient by employing procedures well known in the art.